Calcium channel blockers are a chemically diverse class of compounds having important therapeutic value in the control of a variety of diseases including several cardiovascular disorders, such as hypertension, angina, and cardiac arrhythmias (Fleckenstein, Cir. Res. v. 52, (suppl. 1), p.13-16 (1983); Fleckenstein, Experimental Facts and Therapeutic Prospects, John Wiley, New York (1983); McCall, D., Curr Pract Cardiol, v. 10, p. 1-11 (1985)).
Calcium channel blockers are a heterogenous group of drugs that prevent or slow the entry of calcium into cells by regulating cellular calcium channels. (Remington, The Science and Practice of Pharmacy, Nineteenth Edition, Mack Publishing Company, Eaton, Pa., p.963 (1995)). The regulation of calcium entry into the cells of the cardiovascular system is of paramount importance to the proper functioning of this system. Cardiac and vascular smooth muscle cells have calcium channels within the cell membrane. Calcium influx through these channels initiates a process of electromechanical coupling which ultimately leads to muscle contraction. The ability to regulate the entry of calcium into cardiac and vascular smooth muscle cells is a powerful therapeutic approach in the treatment of angina and hypertension respectively. Likewise, blocking calcium influx into cardiac tissues and conduction systems provides a useful approach to control certain types of arrhythmia.
Calcium channel blockers are also believed to be useful in the treatment of other disorders in which the regulation of calcium plays a role in normal hemostasis. Such disorders include, for example, pulmonary hypertension, peripheral vascular disease, mild congestive heart failure, hypertrophic subaortic stenosis, protection against ischemic injury, stroke, migraine, tumor resistance to anti-neoplastic drugs, achalasia, esophageal spasms, bronchial asthma, premature labor, dysmenorrhea, and enhancement of success in renal transplantation. (Remington, The Science and Practice of Pharmacy, Nineteenth Edition, Mack Publishing Company, Eaton, Pa., p.963 (1995)).
Most of the currently available calcium channel blockers belong to one of three major chemical groups of drugs, the dihydropyridines, such as nifedipine, the phenyl alkyl amines, such as verapamil, and the benzothiazepines such as diltiazem. While the structure activity relationships (SAR) of the dihydropyridines and the phenyl alkyl amines are well defined and extensively studied, very limited information is available on the SAR of benzothiazepines such as diltiazem. Diltiazem is a chiral molecule, with a seven membered fused-ring system, having a thiazepine, which is fused with a benzene ring. The structure is further characterized by three key functional groups, a 4-methoxybenzyl substituent at position “2”; an actoxy ester at position “3”; and positions “4” and “5” forming an amide function with N,N-dimethylaminoethyl substitution at the amide nitrogen. Scientists at central research laboratory at Osaka, Japan, synthesized a series of potent calcium channel blockers in which the seven membered ring of diltiazem was replaced with 6- and 5- membered fused-ring systems. These two new classes of calcium channel blockers, the benzothiazine and benzothiazole respectively (Yamamoto, K., J. Med. Chem., v.31, p. 919-930 (1988); Fujita, M., J. Med. Chem., v. 33, p. 1898-1905 (1990)) demonstrated potent calcium channel blocking activity. Some of these compounds even demonstrated more tissue selectivity toward calcium channels in blood vessels.